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Research Rut

Beefed Up Federal AIDS Vaccine Program Found to Suffer from Lingering Shortcomings

April 2000

Tethered to the Past

The first two decades of AIDS vaccine research have been characterized by a series of disappointments and setbacks. Indeed, while at the epidemic's outset many predicted that it would be easier to develop a vaccine for HIV than effective treatments, the reverse has turned out to be the case. Initial approaches to HIV vaccine development foundered due to the unexpected complexity of HIV-1 as an immunogen and, in part, due to somewhat simplistic research approaches. Now, however, with new insights into HIV pathogenesis, new research tools, new resources, and new commitment from the U.S. government, non-governmental and multilateral sectors, AIDS vaccine research is finally getting the attention, resources, and emphasis it deserves. After over a year of often grueling and tedious investigation, TAG's Gregg Gonsalves has completed his comprehensive critique of the U.S. HIV vaccine effort. What follows is the barest summary of his report.

Our goal in preparing this report is to outline the scientific and practical obstacles in the path of developing a safe, effective, globally deployable AIDS vaccine; to examine the AIDS vaccine research programs funded by the NIH -- taking 1998 as a single, comprehensive snapshot -- and to recommend methods of overcoming those obstacles in order to accelerate the discovery, development, and deployment of an effective vaccine.

It is our belief that a vaccine is most likely to emerge from a creative and rigorous synthesis of basic research in human and non-human primate immunology and in HIV virology, with animal and clinical studies of vaccine candidates, delivery routes and adjuvants. We hope that by examining the scientific issues faced in basic, animal, and clinical HIV vaccine research, we can contribute to overcoming the obstacles and thus contribute to a revitalized, accelerated, intensified vaccine effort.

We surveyed the published scientific literature in order to get a sense of the progress in the field and the unanswered questions that are facing the scientific community. We also interviewed more than two dozen leading researchers, asking them what they thought were the most pressing scientific issues in vaccine research and what practical problems might be impeding progress toward developing a vaccine for HIV infection. Finally, we pored over the listings and abstracts of grants funded with AIDS vaccine research dollars during federal fiscal year (FY) 1998. We looked at FY 1998 because that was the most recent year for which complete records were available. Whenever possible, we have tried to comment on newer projects and programs where they are relevant.

We have divided the report into three major sections: basic research, animal-based research, and clinical trials. Several major recommendations and overarching themes emerged from our analysis. These major themes include advocating for:

continuing increases in research funding for all three major areas of HIV vaccine research;

intensified investment in human immunology;

an expanded, more cohesive animal-based research program, and;

maintaining a strong, scientifically rigorous domestic and international clinical research program.

It is of great concern to us that our findings and recommendations echo many of those made by researchers and advocates about the NIH AIDS vaccine program in the Levine report almost four years ago. While the NIH AIDS vaccine program has grown substantially in recent years and been considerably restructured, there are lingering problems in the program that have yet to be adequately addressed.

Finding a way to control the global AIDS epidemic should be one of the world's highest public health priorities. Although behavioral interventions and public health measures such as safer sex campaigns, antiretroviral therapy initiated during pregnancy, and the surveillance of the blood supply remain our best current options, HIV vaccines may be the only cost-effective way to ultimately end transmission of HIV worldwide. Despite increased attention in the media, speeches from President Clinton, and increased budgets for HIV vaccine research, government and private investor funding for HIV vaccine research is still relatively small. Funding in 1998 to research and develop HIV vaccines by NIH and all other U.S. agencies amounted to only about 10% of overall AIDS research funding.

The $148 million spent by the NIH in 1998 for HIV vaccine research was widely distributed, supporting research through 647 grants and contracts to more than 140 institutions and easily more than 1,000 researchers. NIH funding thus encompassed an enormously broad range of researcher ideas. Although widely distributed, NIH funding wasn't randomly scattered. The 1998 NIH effort included several targeted, concerted funding initiatives to address critical research questions, refine research techniques, make new assays and reagents widely available, and support networks and collaborations.

It is our contention that the NIH AIDS vaccine research effort -- including its basic, animal, and clinical aspects -- can utilize continuing funding increases in line with those obtained in the past few years. Where will this money come from? In recent years, NIH has received unprecedented increases in its annual budget. AIDS research too has continued to grow at a robust rate. With the NIH budget set to double by 2002, additional spending on AIDS vaccine research should be possible without reducing resources devoted to other areas of research on HIV infection, or on other high priority basic and clinical research areas.

Basic Research

While great strides have been made in basic research on HIV infection, there are many unanswered questions about what kind of immune response to HIV a successful vaccine will have to induce -- and about how to engender that response. Even today, none of the current vaccine candidates furthest along in development is capable of inducing long-lasting, broadly cross-reactive, vigorous antibody and cellular immune responses in humans. While there is a healthy investment in immunology at NIH, most of that work is being done in mice. A robust, new investment in clinical immunology is needed to understand how we can generate effector and memory neutralizing antibody and cytotoxic T-cell responses at mucosal sites. NIH should increase resources devoted to mucosal immunology and vaccinology, and should help bring new researchers into the field by initiating new training programs in this area. In addition, clinical research on mucosal delivery of new candidate vaccines should be made a priority by the new Vaccine Trials Network.

NIH needs to support additional work on antigen delivery in both primates and humans. NIH should expand access to monkeys through supporting new breeding programs and investing in the development and production of reagents for primate experiments. Study sections need to be more generous in the level of funding they will support for primate studies. Resources devoted to clinical and human immunology need to be increased, with a special emphasis on bringing young physicians into the field to study some of these unanswered questions in a clinical setting.

Given the difficulty in sustaining both antibody and cellular responses with current immunogens, NIH should invest additional resources in the study of immunological memory in humans. NIH should coordinate its non-AIDS work in this area with basic research on HIV vaccines. NIH needs to break free of the tether of outdated approaches to virus neutralization using monomeric subunit vaccines in both basic and clinical research. While several groups are working on better envelope-based immunogens, research in this area can be expedited if NIH supports fast-track testing of these new products in macaques and in humans.

Animal-Based Research

The SIV and SHIV macaque models offer important tools to address many basic scientific questions about the primate immune system, the immune responses to retroviral infection, and the relative efficacy of different vaccine concepts. Unfortunately, using macaques in research is expensive; these animals are a precious and scarce resource. To date, most of the studies performed in macaques have been small, pilot studies using different assays, different vaccine candidates, different routes of challenge and different challenge viruses. With small numbers and varying research conditions, it is hard to compare animal-based research studies and get a sense of the big picture. NIH is just now beginning to initiate a large, comparative study of four vaccine approaches in macaques. This is a good first step, but NIH needs to make greater resources available for animal-based research and to encourage a coordinated, rational approach to animal studies. The National Center for Research Resources (NCRR) has been negligent and unresponsive to criticisms from the Levine Committee and others regarding the administration of the Regional Primate Research Centers and other primate colonies. NCRR should be catalyzing progress in this area rather than defending its bureaucratic turf.

Large, comparative studies of vaccines in macaques are critical to assess and optimize candidate immunogens for further testing in humans. NIH should streamline the mechanisms for initiating these trials and provide sufficient resources for their expeditious conduct so that the information gathered can be quickly integrated into decision making.

Clinical Trials

NIH has supported clinical research on HIV vaccines for more than a decade. The programs supported have evaluated candidate vaccines supplied by industry for both safety and immunogenicity. So far, NIH has not initiated any phase III efficacy studies (a single, industry-sponsored international study of the VaxGen gp120 subunit envelope protein is ongoing). The current phase I/II NIH-supported clinical trials programs need to be maintained in the United States and abroad; however, these programs need to refocus their efforts on phase I and II studies of novel vaccine concepts rather than pursuing further study of vaccine candidates that have shown little promise in preclinical, animal, or early human testing. In addition, the clinical trials programs should continue developing closer ties to the basic scientific community to ensure more bi-directional collaboration between "bench" and clinic in HIV vaccine research.

NIH needs to directly fund development of products to feed into clinical evaluation. NIH should expand direct contracting with companies to develop HIV vaccine candidates, such as newer versions of Modified Vaccinia Ankara (MVA), Venezuelan Equine Encephalitis (VEE), Adeno-Associated Virus (AAV), and attenuated salmonella vectors. The NIH should encourage optimization of current vaccine candidates and be willing to discourage work in outdated vaccine concepts that have performed poorly in preclinical, animal or early human studies.

NIH should ensure that the new HIV Vaccine Trials Network and the vaccine clinical trial activities of the Vaccine Research Center, the NIH intramural trial site, and the perinatal sites have the capacity for an adequate number of phase I, II, and III trials during the coming five years. The advancement of candidate immunogens along the vaccine clinical development pipeline has to be driven by science and not by political expediency or industry demands.